Alder Products Research Articles

ChemInform Abstract: Direct Enantioselective Synthesis of Bicyclic Diels—Alder Products.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Direct Enantioselective Synthesis of Bicyclic Diels–Alder Products

AbstractThe direct amine‐catalyzed enantioselective Diels–Alder reaction between α,β‐unsaturated cyclic ketones and nitroolefins is presented. A simple diamine catalyzes the asymmetric Diels–Alder reaction with high stereoselectivity and furnishes the corresponding Diels–Alder adducts in good to high yields with >25:1 dr and up to 86 % ee. The study demonstrates a convenient entry to functionalized bicyclic molecules contaning four stereocenters that are formed with excellent diastreoselectivity and good to high enantioselectivity.

Metal‐Free Triazole Formation as a Tool for Bioconjugation

The development of selective and site-specific bio-orthogonal conjugation methods is an important topic in chemical biology. A wide range of methods, such as the Staudinger ligation, native chemical ligation, genetic incorporation, expressed-protein ligation, Huisgen azide–alkyne cycloaddition, and the Diels–Alder ligation are currently employed in the selective modification of proteins and other biomolecules. In recent years, the Cu-catalyzed variant of the Huisgen 1,3-dipolar cycloaddition, also referred to as “click reaction”, has been increasingly applied in various fields of chemistry as a versatile and mild ligation method. This method allows for the synthesis of complex materials, which include bioconjugates, glycopeptides, functionalized polymers, virus particles, and therapeutics. However, due to the toxicity of the copper catalyst to both bacterial and mammalian cells applications that involve in vivo ligation are limited. In order to circumvent the use of copper ions, Bertozzi and co-workers have devised a strain-promoted [3+2] cycloaddition reaction that involves azides and a strained cyclooctyne derivative. Recent reports by Ju et al. have also shown successful applications of copper-free 1,3-dipolar cycloaddition by using either elevated temperatures or electron-deficient alkynes. We envisioned that the combination of ring strain and electron deficiency, as occurs in oxa-bridged bicyclic systems 2a and 2b, could also lead to an increased reactivity toward [3+2] cycloaddition reactions. Here, we report a spontaneous tandem [3+2] cycloaddition–retro-Diels–Alder ligation method that results in a stable 1,2,3-triazole linkage. This methodology can be applied to biomacromolecules that contain various functional groups under physiological conditions. The oxabridged bicyclic systems 2a and 2b were prepared by a Diels– Alder reaction of substituted propiolates with furan (Scheme 1). Subsequent hydrolysis provided the desired carboxylic acid derivatives 3a and 3b, in excellent yield. To compare the reactivity of Diels–Alder products 2a and b with the corresponding alkynes, [3+2] cycloaddition reactions were performed under ambient conditions by using benzyl azide, and monitored over time with H NMR spectroscopy (Figure 1). The oxanorbornadienes 2a and 2b and their respective alkynes provided identical 1,4,5-substituted triazoles to the products.

Phosphine‐Catalyzed Cycloadditions of Allenic Ketones: New Substrates for Nucleophilic Catalysis.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Thermal C2−C6 Cyclization of Enyne−Allenes. Experimental Evidence for a Stepwise Mechanism and for an Unusual Thermal Silyl Shift

Enyne-allenes 4a-c bearing various cyclopropyl systems as radical clock reporter groups at the allene terminus have been synthesized and subjected to thermal C2-C6 cyclization. The ratio of ene versus formal Diels-Alder products could be rationalized on the basis of steric effects. Only the thermolysis of 4c, equipped with the fast diphenylcyclopropylcarbinyl radical clock, afforded a 1,3-butadienyl benzofulvene clearly formed via cyclopropyl ring opening. This finding provides unambiguous evidence for a stepwise mechanism of the C2-C6 cyclization making it possible to suggest a lifetime for the intermediate diradical of >1x10(-10) s (at 170 degrees C). An interesting corollary was the isolation of an unexpected silyl shift product in the thermolysis of all three enyne-allenes that allows explanation of the loss of the TIPS group in some of the Diels-Alder products. For a full understanding of the mechanism, silyl and hydrogen shift processes were interrogated using DFT.

Control of stereoselectivity in an enzymatic reaction by backdoor access.

Sneaking in: The active site of a Diels–Alder ribozyme features two different “doors” through which the diene may enter. Depending on which door is used, either of the two enantiomeric Diels–Alder products is synthesized selectively. Enantioselectivity can be modulated by controlling access to the ribozyme's active site. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2006/z503280_s.pdf or from the author. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Ene Reaction of Arynes with Alkynes

Arynes, generated in situ from ortho-silylaryl triflates, undergo ene reaction with alkynes possessing propargylic hydrogen in the presence of KF/18-crown-6 in THF at room temperature to give substituted phenylallenes. Various terminal and internal alkynes as well as different arynes can be used to give the corresponding phenylallenes in good to moderate yields. The reaction of alkyne without propargylic hydrogen gave an acetylenic C-H addition product (a phenylalkyne) and a dehydro Diels-Alder product (a phenanthrene).

Preparation and Diels–Alder reaction of carbosilane dendrimer with conjugated diene

The carbosilane dendrimers with 12, 36, 108 and 324 diene groups on the periphery have been prepared. The first generation with 12 diene groups which react with enes such as N-ethylmaleimide, 1,4-naphtoquinone, and tetracyanoethene has produced the Diels–Alder products (DA) on the dendritic periphery. The NMR and MALDI-TOF mass spectra have characterized the DA products. The unified dendritic character has been observed by gel permeation chromatography.

Simultaneous accumulation of both skeletal and appendage-based diversities on tandem Ugi/Diels–Alder products

Diversity-oriented organic synthesis (DOS) is a key concept for construction of skeletally diverse small molecule libraries to discover drug-like small molecules. Here, we describe a DOS class to transform a complex 7-oxanorbornene skeleton, which is readily accessible by a tandem Ugi/Diels–Alder reaction, into two heterotricycle skeletons selectively by using tandem ROM/CM/RCM reaction. In the present study, the mode of cyclization is pre-encoded by building blocks used in the complexity-generating tandem Ugi/Diels–Alder reaction. Since variable alkenes can be used in the CM reaction, our approach can be extended to construct both skeleton- and appendage-diverse small molecule libraries.

Tricarbonyl(naphthoquinone)chromium: Synthesis and Application in [4+2] Cycloaddition Reactions

AbstractTricarbonyl(naphthoquinone)chromium (9) has been prepared in an 82 % overall yield by direct complexation of TBS‐protected naphthohydroquinone (6) and subsequent deprotection/oxidation. Complex 9 underwent [4+2] cycloaddition reactions with a series of dienes to give products in good to excellent yields. The cycloaddition reaction revealed that the tricarbonylchromium fragment exhibits perfect endo selectivity and has an anti‐directing role, as established by X‐ray analyses of the Diels–Alder products 10–13. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Diels–Alder reaction of anthracene on carbosilane dendrimer

The dendritic macromolecule with 4, 8, 16 and 32 bicyclo end groups on the periphery has been created by the Diels–Alder reaction of anthracene and maleimide. The dendritic skeleton with triple bonds has been prepared by the hydrosilation and the alkynylation of bis(phenylethynyl)dimethylsilane as a core. The peripheral anthracene on dendrimers has been substituted by the reaction of chlorosilyl groups containing dendritic generations and 9-anthracenecarbinol. NMR and MALDI-TOF mass spectrum has characterized these Diels–Alder products.

Unexpected chlorination of angularly annelated [2.2]paracyclophanes during DDQ oxidation

DDQ treatment of the Diels–Alder products 1 unexpectedly led to chloroderivatives 2. Chlorination did not occur during DDQ treatment of the fully aromatised compounds 3. These results point out that DDQ acted as an oxidant and source of chlorine.

The High‐Intrinsic Diels—Alder Reactivity of (‐)‐Galiellalactone; Generating Four Quaternary Carbon Centers under Mild Conditions.

The Interleukin-6 (IL-6) responsive JAK/STAT pathway seems to be correlated with major diseases such as chronic inflammation, arteriosclerosis, liver fibrosis, Parkinson and Alzheimer disease. In order to take a look at (−)-galiellalactone as a potential low-molecular-weight lead structure for non-proteinogenic IL-6 antagonists we carried out a microderivatization program that was aiming at bioactive congeners of the natural product and a preliminary structure-activity relationship. During this effort, galiellalactone showed reactivity generally governed by convex-concave face selectivity. O-Acyl derivatives of galiellalactone turned out to be precursors of bis(dehydratogaliellalactone), a novel oligocyclic Diels−Alder product of complicated architecture. During this extraordinary Diels−Alder-type conversion four quaternary carbon centers were generated at room temperature under mild conditions in a regio- and stereoselective fashion. The novel Diels−Alder transformation was used for a stereoselective hetero-derivatization of the natural product leading to an aza congener of altered IL-6 antagonistic activity in HepG2 hepatoma cells. The absolute (4S,5aR,7aR,7bS) configuration of natural (−)-galiellalactone was confirmed by X-ray crystallography with Cu-Kα radiation. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Synthesis of helical [2.2]paracyclophanes containing carbocyclic and heterocyclic five-membered rings

The preparation of a [2.2]indenoparacyclophane-based diene is described. Diels–Alder cycloadditions of this diene with N-methylmaleimide, N-phenylmaleimide and maleic anhydride occurred in good yields and anti-diastereoselectively only under high pressure conditions. Heterohelicenophanes were prepared by dehydrogenation of the Diels–Alder products with 10% Pd/C catalyst. A new helicenophanequinone was obtained by the reaction between the diene and 1,4-naphthoquinone.

Detection of Transient Radical Cations in Electron Transfer-Initiated Diels−Alder Reactions by Electrospray Ionization Mass Spectrometry

The coupling of a simple microreactor to an atmospheric pressure ion source, such as electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI), allows the investigation of reactions in solution by mass spectrometry. The tris(p-bromophenyl)aminium hexachloroantimonate (1(*)(+)SbCl(6)(-))-initiated reactions of phenylvinylsulfide (2) and cyclopentadiene (3) and of trans-anethole (5) and isoprene (6) and the dimerization of 1,3-cyclohexadiene (8) to give the respective Diels-Alder products were studied. These preparatively interesting reactions proceed as radical cation chain reactions via the transient radical cations of the respective dienophiles and of the respective Diels-Alder addition products. These radical cations could be detected directly and characterized unambiguously in the reacting solution by ESI-MS-MS. The identity was confirmed by comparison with MS-MS spectra of the authentic radical cations obtained by APCI-MS and by CID experiments of the corresponding molecular ions generated by EI-MS. In addition, substrates and products could be monitored easily in the reacting solution by APCI-MS.

Enantiomerically pure Diels–Alder cycloadducts from aldohexose-derived dihydropyranones

The thermal and Et 2O·BF 3-catalyzed Diels–Alder additions of 2,3-dimethylbutadiene and cyclopentadiene to (2 S,6 S)-6-acetoxymethyl-2-(2-propyloxy)-2 H-pyran-3(6 H)-one 1, derived from d-galactose, afforded the corresponding enantiomerically pure tetrahydrobenzopyrones resulting from the addition of the diene to the α or β face of 1. The facial and endo– exo selectivities in the formation of the adducts, and their yields, are influenced by the diene and the reaction conditions employed. In particular, low overall yields were obtained in the Lewis acid-promoted reactions. This was attributed to the presence of a Lewis base (an acetoxymethyl group) in the pyranone 1. Therefore, (2 R,6 S)-6-methyl-2-(2-propyloxy)-2 H-pyran-3(6 H)-one 7, which possesses a C-6 methyl substituent instead of an acetoxymethyl, was prepared from l-fucose and subjected to the Et 2O·BF 3-catalyzed addition of cyclopentadiene. As expected, a good yield (74%) of the corresponding Diels–Alder product was obtained, with excellent β- and endo-diastereoselectivities.

Application of Furan as a Diene: Preparation of Condensed 1,3‐Oxazines by Retro‐Diels−Alder Reactions

Abstract(Di‐exo‐3‐amino‐7‐oxabicyclo[2.2.1]hept‐5‐en‐2‐yl)methanol (3) was treated with oxo carboxylic acids [p‐toluoylpropionic acid, cis‐ or trans‐(p‐toluoyl)cyclohexanecarboxylic acid, ‐benzoic acid or methanobenzocyclooctenecarboxylic acid] to furnish the oxanorbornene‐fused pyrrolo[1,3]oxazine 4, the isoindolo[1,3]oxazines 5 and 6, and the methanobenzocyclooctenepyrrolo[1,3]oxazine 10, together with the retro‐Diels−Alder products pyrrolooxazinone 7, oxazinoisoindolones 8 and 9, and oxazinopyrrolobenzocyclooctene 11. On reflux in chlorobenzene, furan was released from the oxanorbornene heterocycles 5 and 10 to give the retro‐Diels−Alder products. The structures of the new compounds were established by NMR spectroscopy and also (for 6 and 9) by single‐crystal X‐ray structure determination. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

The High‐Intrinsic Diels−Alder Reactivity of (−)‐Galiellalactone; Generating Four Quaternary Carbon Centers under Mild Conditions

AbstractThe Interleukin‐6 (IL‐6) responsive JAK/STAT pathway seems to be correlated with major diseases such as chronic inflammation, arteriosclerosis, liver fibrosis, Parkinson and Alzheimer disease. In order to take a look at (−)‐galiellalactone as a potential low‐molecular‐weight lead structure for non‐proteinogenic IL‐6 antagonists we carried out a microderivatization program that was aiming at bioactive congeners of the natural product and a preliminary structure‐activity relationship. During this effort, galiellalactone showed reactivity generally governed by convex‐concave face selectivity. O‐Acyl derivatives of galiellalactone turned out to be precursors of bis(dehydratogaliellalactone), a novel oligocyclic Diels−Alder product of complicated architecture. During this extraordinary Diels−Alder‐type conversion four quaternary carbon centers were generated at room temperature under mild conditions in a regio‐ and stereoselective fashion. The novel Diels−Alder transformation was used for a stereoselective hetero‐derivatization of the natural product leading to an aza congener of altered IL‐6 antagonistic activity in HepG2 hepatoma cells. The absolute (4S,5aR,7aR,7bS) configuration of natural (−)‐galiellalactone was confirmed by X‐ray crystallography with Cu‐Kα radiation. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Influence of species proportion and timing of establishment on stem quality in mixed red alder – Douglas-fir plantations

The relationships among stand structure, Douglas-fir (Pseudotsuga menziesii (Mirb.) Franco) branch characteristics, and red alder (Alnus rubra (Bong.)) stem form attributes were explored for 10- to 15-year-old trees growing in mixed Douglas-fir – red alder plantations. Treatments included a range of species proportions, and red alder was either planted simultaneously with Douglas-fir or after 5 years. Both replacement effects (total stand density held constant) and additive effects (stand density doubled) of competition were considered. When the two species were planted simultaneously and red alder proportion was low, red alder trees had low crown bases and much stem defect (lean, sweep, and multiple stems). Douglas-fir grew slowly when the two species were planted simultaneously. When red alder planting was delayed, species proportion did not affect red alder stem form, and height to the base of the Douglas-fir live crown decreased with increasing red alder proportion. Doubling Douglas-fir density increased the height to the base of the Douglas-fir live crown; however, doubling stand density by adding red alder did not affect Douglas-fir crown height. Douglas-fir lumber coming from mixed stands may be inferior because of the changes in knot characteristics associated with these different patterns of crown recession. In stands with a low proportion of red alder, red alder product recovery may be compromised because of the stem defects described above.

Dehalogenation of o‐Dihalogen Substituted Arenes and α,α′‐Dihalogen Substituted o‐Xylenes with Lanthanum Metal.

AbstractFor Abstract see ChemInform Abstract in Full Text.